Advancing the Treatment Paradigm for mCRPC: Insights into Combination Therapy and Future Directions

Panelists discuss how the evolving treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) encompasses multiple therapeutic options including novel hormonal agents, chemotherapy, and targeted therapies while highlighting persistent challenges in treatment sequencing, drug resistance, and the need for improved biomarker-driven approaches to optimize patient outcomes.

Panelists discuss how radiopharmaceuticals like lutetium-177 prostate-specific membrane antigen (PSMA) may be preferred over systemic therapy in patients with prostate cancer who have high PSMA expression, multiple bone metastases, and limited visceral disease, particularly after progression on standard therapies like androgen receptor pathway inhibitors and taxane-based chemotherapy.

Panelists discuss how the PEACE-3 trial demonstrated meaningful clinical benefits with the combination of radium-223 and enzalutamide compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), showing both improved radiologic progression-free survival and a significant overall survival advantage of 7.3 months.

Panelists discuss how the combination of radium-223 and enzalutamide (RAD-ENZ) demonstrated a manageable safety profile in PEACE-3, with bone health monitoring and prophylactic bone-targeted therapy being crucial considerations, particularly given the potential impact on future treatment options.

Panelists discuss how adapting the PEACE-3 protocol to real-world US patient populations requires careful consideration of broader patient demographics, comorbidities, and prior treatment histories than were represented in the trial’s relatively strict eligibility criteria.

Panelists discuss how regulatory approval of the radium-223 and enzalutamide combination would likely lead to significant guideline updates, particularly in treatment sequencing recommendations for patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-predominant disease and adequate bone marrow function.

Panelists discuss how patients with bone-predominant mCRPC, good performance status, adequate bone marrow function, and limited visceral disease are ideal candidates for RAD-ENZ combination therapy, particularly when proper bone health monitoring and prophylaxis can be implemented.

Panelists discuss how early implementation of RAD-ENZ combination therapy requires careful consideration of patient characteristics, disease burden, and long-term treatment planning while potentially offering the greatest benefit when initiated before significant disease progression occurs.

Panelists discuss how the phase 3 DORA trial investigates the combination of standard of care darolutamide with radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC), building upon the positive safety profile of novel hormone therapy combinations with radiopharmaceuticals seen in PEACE-3.

Panelists discuss how future trials in metastatic castration-resistant prostate cancer (mCRPC) should focus on developing reliable biomarker-driven treatment selection strategies to optimize sequencing decisions and identify which patients will benefit most from specific therapies or combinations, particularly as the treatment landscape becomes increasingly complex.